MDI 301 is a synthetic retinoid that is similar to all-trans retinoic acid (RA) in its ability to stimulate collagen synthesis and inhibit the major collagen-degrading enzymes in skin. A feature that distinguishes MDI 301 from RA is its lack of irritation when applied topically to skin. Past studies from our laboratory have shown that topical pretreatment of diabetic rats with RA improves the healing of subsequently-induced abrasion wounds. The recently completed Phase I studies of this SBIR grant demonstrated that MDI 301 also improves healing of abrasion wounds in diabetic rats. The Phase II studies build on this. The workplan for the Phase II studies contains three specific aims: First, using the same model of streptozotocin-induced diabetes in rats as used in the initial studies, we will determine the extent to which MDI 301 improves wound-healing in the skin. Second, using organ cultures of human skin obtained from diabetic subjects (skin from both at-risk and non-at-risk sites) we will determine the extent to which MDI 301 affects changes in physiology of human diabetic skin that contribute to successful wound healing. Finally, in aim three, we will continue the safety profiling of MDI 301 necessary for FDA approval. The overall goal of the proposed studies is to determine if topical pretreatment of skin with MDI 301 will, like RA itself, improve healing of subsequently-induced wounds but do so without provoking irritation. If it can be shown that MDI 301 is as effective as RA but without the negative consequence seen with RA, it will provide a better agent for development as a chronic wound preventative.